Prenatal Genetic Diagnosis Unit, Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Ultrasound Obstet Gynecol. 2022 Jul;60(1):59-67. doi: 10.1002/uog.24885.
Prenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly.
This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed using ES to assess its ability to detect copy-number variants (CNVs).
CMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty-six CMA-negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non-significantly higher compared with non-recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non-causative CNVs.
In our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
产前检出的中枢神经系统（CNS）异常具有诊断挑战性。本研究比较了大片段基因组重排测序（ES）和染色体微阵列分析（CMA）在胎儿 CNS 主要畸形中的诊断效能。
这是一项回顾性研究，纳入 114 例因产前超声检出 CNS 主要畸形而终止妊娠（TOP）后行遗传评估的胎儿。所有胎儿均首先行 CMA 分析，CMA 阴性者行 ES 检查。CMA 阳性者行 ES 再分析以评估其检测拷贝数变异（CNV）的能力。
CMA 在 114 例胎儿中检出 11 例（10%）致病性或疑似致病性（P/LP）CNV。86 例 CMA 阴性胎儿行 ES 检查，检出 38 例（44%）P/LP 序列变异。在复发性病例（即曾有受累妊娠的病例）中，P/LP 序列变异的发生率显著高于非复发性病例（12/19 [63%] 比 26/67 [39%]；P=0.06）。在 38 例 ES 诊断病例中，20 例（53%）为遗传所致，具有显著的再发风险。10 例 CMA 阳性病例的 ES 再分析显示，用于序列变异分析的生物信息学分析流程也可检出所有 P/LP CNV 以及 3 例已知的非致病性 CNV。
在本研究中，ES 在严重 CNS 结构畸形胎儿中提供了高的诊断率（>50%），这可能部分归因于该研究纳入了来自专科转诊中心的 TOP 后病例这一高度选择的病例系列。这些数据表明，ES 可考虑作为产前诊断胎儿 CNS 主要畸形的一线检查方法，可同时检出 P/LP 序列变异和 CNV。鉴于妊娠期间的时间限制和未来妊娠中再发的风险，这一点尤其重要。 © 2022 作者。超声在妇产科由约翰威立父子公司出版代表国际妇产科超声学会。
